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Patients diagnosed with amyotrophic lateral sclerosis (ALS) live an average of three years after diagnosis, but some survive mere months and others decades. How to explain this tremendous variability? Scientists are searching for genetic factors that might account for it, and in the May 31 JAMA Neurology, John Powell and Isabella Fogh at King’s College London report finding genetic variations in two regions of the genome tied to duration of ALS. Single nucleotide polymorphisms (SNPs) in the introns of two genes—CAMTA1 and IDE—shortened survival time by eight and four months, respectively.

“If this finding is real, then understanding what these genes do may help us develop drugs that slow the progression of ALS,” wrote Richard Bedlack, Duke ALS Clinic in Durham, North Carolina, to Alzforum. He cautioned, however, that the study did not control for use of riluzole, the only drug approved for ALS, or clinical care such as non-invasive ventilation, which can both improve survival. “This study should be repeated using a model that accounts for these treatments,” he suggested.

Previous genome-wide association studies (GWAS) have identified genetic variants that modify survival among ALS patients, but some have not stood up to further scrutiny. For instance, people with sporadic ALS who have two copies of an expression-lowering variant of the kinesin-associated protein 3 (KIFAP3) reportedly lived 14 months longer than those without it, but later attempts to replicate that finding failed (Landers et al., 2009; van Doormaal et al., 2014; Traynor et al., 2010). Other studies have implicated variations in the UNC13A, EPHA4, and D-amino acid oxidase (DAO) genes in determining how long ALS patients survive (Diekstra, 2012; Van Hoecke et al., 2012; Cirulli et al., 2015). Predicting survival time is important, as it helps patients and families plan for what’s to come and could help stratify patients for clinical trials.

Fogh and her genetics colleagues from both sides of the Atlantic wanted to confirm prior findings by conducting the largest ALS GWAS to date. They pooled genotype data from seven independent published data sets on 4,256 sporadic ALS patients from Europe and the United States, including more than 7,000,000 SNPs in their analysis. Though some data sets included far fewer, the scientists in many cases were able to infer which SNPs were there by detecting neighboring ones that tend to be co-inherited—a process known as imputation.

The authors used Cox proportional hazards regression modeling to determine whether any SNPs associated with ALS survival. This type of analysis allowed them to account for age at onset and whether the initial symptoms affected speech and swallowing or limb strength and respiration—both of which are known to predict the speed of disease progression. It also allowed them to include 1,131 patients still living with the disease and incorporate information about their continued survival. Patients averaged an age at onset of 59 years, declared European ancestry, and had no family history of motor neuron diseases. Fogh and colleagues obtained the necessary clinical information from medical records and death certificates.

Only the IDE and CAMTA1 loci popped up as significant. The former encodes insulin-degrading enzyme, a zinc metallopeptidase that breaks down insulin and amyloid-β. It sits on chromosome 10, in a region where the researchers found the most influential SNP, rs139550538, located in an IDE intron. People with a TT genotype (the major allele) at this locus outlived people who carried an AA or TA by about eight months. The CAMTA1 gene, which encodes the calmodulin-binding transcription activator 1, lies on chromosome 1, where four SNPs reached and 87 SNPs approached significance—all in introns 3 and 4 of the gene. For the top-ranked SNP, rs2412208, one or two G alleles (the minor allele) shortened survival by four months relative to TT carriers.

This GWAS found no association with longevity for KIFAP3, EPHA4, DAO, or UNC13, although one SNP in the latter approached significance.

It is unclear why CAMTA1 or IDE would be involved in ALS progression. A case can be made for CAMTA1, since disruptions in the gene have been tied to non-progressive congenital cerebellar ataxia, gait instability, and impaired episodic memory (Thevenon et al., 2012; Shinawi et al., 2015; Huentelman et al., 2007). CAMTA1 mouse knockouts also have severe ataxia (Long et al., 2014). These associations hint that cerebellar degeneration resulting from CAMTA1 defects may worsen ALS, the authors wrote. However, rs2412208 lies in an intron and the function of that portion of the gene is still in question, said Powell. “Much work remains to figure out the causative allele and the biological basis for its involvement,” he said.

Bedlack noted that the effect size for each gene was small, with a hazard ratio below two. The authors acknowledged this, and that the effect size works out to be similar to that of treatment with riluzole. Powell agreed that while genetics may explain some of the variation in survival, other factors may be equally or more important. As Nathan Staff of the Mayo Clinic in Rochester, Minnesota, noted in an accompanying editorial, the immune system, environmental factors, and their epigenetic consequences all influence the severity and progression of ALS. “In the end, large GWAS may be underpowered to detect susceptibility genes in ALS, because ALS itself may represent more than one disease and pathomechanism,” he wrote.

This study represents an incredible amount of work, said David Ennist, Origent Data Sciences, Vienna, Virginia. That these authors found genetic modifiers of survival with just genomic data bodes well for other studies that plan to incorporate clinical measures, demographics, and information about gene expression. These projects include Answer ALS, which aims to collect comprehensive clinical and genetic data on 1,000 ALS patients and generate induced pluripotent stem cells from each, and Project MinE, which will analyze the DNA of 15,000 ALS patients and 7,500 controls (Jul 2015 news). “Within five years, we may have a really good understanding of ALS and all its forms,” he told Alzforum. “Some of these variants are very rare, so as we examine bigger and more comprehensive datasets, we’ll be able to derive more definitive findings.”

Bedlack added that it would be interesting to examine the genetics of those whose disease progression temporarily halted or even reversed (Bedlack et al., 2016).—Gwyneth Dickey Zakaib

Comments

I have personally seen more than 2,000 patients with ALS in the past 16 years. I believe the variability in the disease holds important clues to figuring out how to slow, stop, or reverse it. This interesting paper suggests that variations in two genes, IDE and CAMTA1, are associated with slightly longer survival. If this finding is real, then understanding what these genes do may help us develop drugs that slow the progression of ALS.

The major strength of this paper is its large sample size. This multinational group of authors should be commended for their collaboration.

There are, however, some weaknesses. The biggest one is that the model used did not account for between-patient variability in the use of treatments known to affect survival such as riluzole, multidisciplinary care, and most importantly non-invasive ventilation (which has the largest effect on survival). The authors argue that stratification by country reduced the risk of bias from riluzole and multidisciplinary clinic use. It is not clear to me that stratification by country can correct this issue. In my opinion, this study will need to be repeated using a model that accounts for these three treatments. As with all ALS studies, there is likely to be a referral bias here since only a small percentage of patients enroll, and these patients may be different from those who do not enroll. This will create problems with generalizability. It is likely that ALS patients with the most extreme (and interesting) phenotype—those who stop progressing or even reverse with recovery of lost motor function—were not included in this study since many of them no longer attend ALS clinics. Finally, it is disappointing that the effect size for each of these genes was so small (hazard ratios less than 2) and that this study could not replicate the findings of previous work that suggested variations in Kifap3, EphA1, and/or DAO genes might influence survival.

I look forward to seeing this study replicated using a model that accounts for treatments that can effect survival. Even more, I look forward to a study that focuses on extreme ALS phenotypes including patients whose disease seems to stop progressing or reverses with recovery of lost motor functions.